Growth failure is common in children with chronic renal failure (CRF). Linear growth rate reflects a balance between the actions of growth stimulators such as growth hormone (GH) and insulin-like growth factor (IGF)-I, and the actions of growth inhibitors, on mitogenic pathways of growth plate chondrocytes. GH levels, IGF-I levels and IGF-I bioactivity are normal in CRF sera, suggesting that CRF is associated with an excess of growth inhibitors and a failure of normal growth-promoting pathways to compensate for these inhibitors. CRF serum has an excess of IGF binding proteins (IGFBPs)-1 and -2; each is a potent inhibitor of IGF action in vitro. GH therapy stimulates growth of CRF children and at the same time lowers IGFBP-1 levels, suggesting that IGFBP-1 is a growth inhibitor. Preliminary data also show that GH raises levels of IGFBP-3 fragments. Unlike IGFBP-1, which blocks IGF action by competing with IGF-1 receptors for IGF binding, the IGFBP-3 fragments appear to bind IGFs weakly, and may stimulate growth by releasing IGF's to IGF-1 receptors. The objectives of this proposal are to identify those IGFBPs which inhibit growth and those which stimulate growth in CRF, and to study to regulation of each; this may suggest ways to maximize growth stimulation and minimize inhibition in CRF and other growth failure states: 1. In a multicenter trial of GH therapy in CRF children, sera will be assayed for IGFBPs. By relating these levels to growth response, the studies should confirm that IGFBP-1 and -2 are potential growth inhibitors, and IGFBP-3 fragments are potential growth stimulators. 2. The effect of high IGFBP-1 levels on linear growth will be studied by using the albumin enhancer/promoter to overexpress the human IGFBP-1 gene in livers of transgenic mice; it is likely that mice overexpressing IGFBP-1 will not grow as well as littermate controls. 3. Since IGFBP-1 is regulated at the level of hepatic transcription under the dominant inhibitory control of insulin, studies will focus on cloning genes of proteins which mediate the inhibitory effect of insulin on IGFBP-1 transcription; understanding the function and regulation of these proteins may suggest ways to suppress IGFBP-1 production. 4/ An IGFBP-3 antibody linked to an affinity column will be used to purify IGFBP-3 fragments; these fragments will be analyzed for their IGF-I binding affinity and for their ability to modify IGF-I effects on fibroblasts in vitro. These fragments are likely to bind IGF-I with low affinity and to potentiate IGF-I-mediated effects; this will suggest that they may potentiate GH-initiated, IGF- mediated growth stimulation in vivo, and that factors regulating production of these fragments need to be identified.
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